This application is a 371 of PCT/FR00/03174 filed Nov. 15, 2000.
The present invention relates, by way of novel industrial products, to xcex2-D-5-thioxylose derivatives, more particularly to the 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside derivatives of formula I below. It further relates to the method for the preparation of these novel products and to their use in therapeutics.
EP-A-0421829, especially Table I of said document, discloses benzopyranone xcex2-D-thioxyloside compounds of formula Io: 
in which:
X is O or S,
Y is especially H or COCH3,
R1 is especially C1-C4-alkyl and
R2is particularly H, C1-C4-alkyl or halogen, which are presented as being useful in therapeutics in view of their effects in the prevention or treatment of disorders of the venous circulation, especially venous thrombosis.
In particular, the compound 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside (formula Io in which X=O, Y=H, R1=CH3 and R2=H), administered orally, exhibits a remarkable activity at doses of 6 mg/kg and above in the sense that it reduces the formation of a venous thrombus by more than 80%. This activity, which is obtained after oral administration, is extremely valuable in the case of the most common use of such products, which generally corresponds to a preventive treatment.
In fact, the products commonly used at the present time in this field of therapeutics, for example anticoagulants, namely normal heparins and low molecular heparins, are not active by oral administration and have to be administered by intravenous or subcutaneous injection. Such a mode of administration, especially in a chronic treatment, is not generally liked by the patient, who prefers to take a tablet or a gelatin capsule orally. From this point of view, the compounds according to EP-A-0421829 represent a certain advance in terms of the patient""s comfort, the risk and the costs associated with the mode of administration. It should also be pointed out that, in contrast to the products already in use, these compounds do not increase the risk of a hemorrhage.
However, the compounds described in EP-A-0421829 are not sufficiently soluble to allow them to be administered by injection. Thus they cannot be used in cases where injection is the only possible route of administration or if it seems preferable for the sake of convenience to administer one of these compounds in association with other drugs by perfusion.
According to the invention, a novel technical solution is proposed for solving the above-mentioned solubility problem. This novel solution involves novel 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside derivatives which have a better solubility in the customary solvents, especially injectable solutions, while at the same time retaining an oral activity.
The invention provides, by way of a novel industrial product, a compound which is characterized in that it has formula I: 
in which R is a linear, branched or cyclic C1-C5-alkyl group, a monounsaturated C2-C3-alkene group, a C2-C3-hydroxyalkyl group or a C3-C6-alkoxyalkyl group.
According to another feature of the invention, the method for the preparation of a compound of formula I is provided, said method being characterized in that it comprises the carbonation reaction of 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside of formula II: 
with a reagent selected from the group consisting of a halogenoformate of formula III: 
and a pyrocarbonate of formula IV: 
in which R is a C1-C5-alkyl group, a C2-C3-alkene group, a C3-C6-alkoxyalkyl group or a C2-C3-hydroxyalkyl group in which the alcohol function is protected by a protecting group, such as a trialkylsilyl group for example, and Hal is a halogen atom (especially F, Cl or Br, the preferred halogen here being chlorine).
This method involves protecting the OH function of the group Rxe2x95x90C2-C3-hydroxyalkyl before carbonation and then deprotecting it after said carbonation.
The procedure is as follows, depending on the nature of the group R. When Rxe2x95x90Rxe2x80x2=a linear, branched or cyclic C1-C5-alkyl group, a monounsaturated C2-C3-alkene group or a C3-C6-alkoxyalkyl group, the reaction II+III or II+IV is carried out.
When Rxe2x95x90Rxe2x80x3=a C2-C3-hydroxyalkyl group, the carbonation reaction of 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside of formula II is carried out with a halogenoformate of formula IIIbis: 
in which Rxe2x80x3 is a C2-C3-hydroxyalkyl group with its OH function protected and Hal is a halogen atom as defined above, and the resulting compound is then subjected to a deprotection reaction of the hydroxyl group, for example by reaction with hydrofluoric acid solution if the protecting group is a trialkylsilyl group, to give the compound of formula I in which R is a C2-C3-hydroxyalkyl group.
According to yet another feature of the invention, on the one hand a pharmaceutical composition is provided which is characterized in that it comprises a therapeutically effective amount of at least one compound of formula I in association with a physiologically acceptable excipient, and on the other hand the use of a compound of formula I is provided which is characterized in that said compound of formula I is used for obtaining an antithrombotic drug intended for therapeutic use to combat disorders of the venous circulation.
Methyl, ethyl, propyl, 1-methylethyl, cyclopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and pentyl groups may be mentioned among the C1-C5-alkyl groups which are suitable according to the invention.
Vinyl and allyl groups may be mentioned among the C2-C4-alkene groups which are suitable according to the invention. In this case a monounsaturated alkene group denotes an aliphatic group containing only one Cxe2x95x90C double bond.
Methoxyethyl, ethoxyethyl, methoxyethoxyethyl and ethoxyethoxyethyl groups may be mentioned among the C3-C6-alkoxyalkyl groups which are suitable according to the invention.
2-Hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl groups may be mentioned among the C2-C3-hydroxyalkyl groups which are suitable according to the invention.
Among the compounds of formula I, which are 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside tricarbonates, those in which R is an ethyl group or a methyl group are preferred.
The compounds of formula I can advantageously be prepared by means of
a) a carbonation reaction in which 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-xcex2-D-xylopyranoside of formula II: 
is reacted with a chloroformate of formula IIIa: 
or a pyrocarbonate of formula IV: 
in which R is a linear, branched or cyclic C1-C5-alkyl group, a monounsaturated C2-C3-alkene group, a C3-C6-alkoxyalkyl group or a C2-C3-hydroxyalkyl group in which the hydroxyl group is protected by a protecting group, especially the t-butyldimethylsilyl group, the reaction being carried out in an anhydrous solvent, such as dimethylformamide for example, in the presence of an aprotic base, such as 4-(dimethylamino)pyridine for example, at a temperature of between 10xc2x0 C. and 80xc2x0 C. for 1 to 10 hours to give the compound of formula I in which R retains the same meaning as in the reagent IIIa or IV; and
b) if necessary, in the case of the preparation of a compound of formula I in which R is a hydroxyalkyl group, a deprotection reaction of the hydroxyl group, especially by reaction with hydrofluoric acid if the protecting group is a t-butyldimethylsilyl group, at room temperature, in a solvent such as acetonitrile for example.
When R is a C2-C3-hydroxyalkyl group, the carbonation reaction is preferably effected by means of a chloroformate. The protecting group of the OH function must be more readily cleavable than the Oxe2x80x94COxe2x80x94O function so that it can be removed during deprotection without affecting said Oxe2x80x94COxe2x80x94O function, the preferred protecting group being a trialkylsilyl group.
The therapeutic composition can be in the form of a solution, or a preparation convertible to a solution, which can be administered by injection, either subcutaneously, or intravenously, or in the form of a perfusion. The therapeutic composition can also be presented in a form which can be administered orally, for example gelatin capsules, tablets or a solution to be taken orally.
The compounds of formula I are useful in therapeutics on account of their antithrombotic activity and are of particular value for the treatment or prevention of disorders of the venous circulation, especially for correcting certain hematological parameters perceptible in the venous system.